US6514953B1ExpiredUtility
Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate
Est. expiryJul 18, 2018(expired)· nominal 20-yr term from priority
A61P 31/12A61P 31/18A61P 31/14A61P 31/00A61P 37/04C07F 9/65515A61K 31/665C07F 9/655
89
PatentIndex Score
79
Cited by
1
References
20
Claims
Abstract
The invention relates to calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate, to processes for its preparation, and to its use in the treatment of diseases caused by retroviruses.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate Form (1).
2. A pharmaceutical composition comprising a compound as claimed in claim 1 together with at least one pharmaceutically acceptable diluent or carrier therefor.
3. A method for the treatment of an HIV infection in a human which comprises administering to said human, an effective anti-HIV infection treatment amount of a compound as claimed in claim 1 .
4. A pharmaceutical composition according to claim 2 in the form of a powder.
5. A pharmaceutical composition according to claim 2 in the form of a suspension.
6. A pharmaceutical composition according to claim 2 in the form of a tablet.
7. A process for the preparation of a compound of formula (I) in a crystalline form,
comprising
i) reacting a compound of formula (II)
with a phosphorylating agent;
ii) reducing the resultant compound with a reducing agent in a suitable solvent; and
iii) adding to the resultant compound a source of calcium ions in the presence of a suitable solvent.
8. A process for the preparation of a compound of formula (I)
comprising dissolving a compound of formula (III)
in a suitable solvent, and adding to the solution water and a source of calcium ions.
9. A process for the preparation of a compound of formula (I)
comprising the reduction of a compound of formula (IV)
in the presence of a suitable reducing agent in a suitable solvent, followed by adding water and a source of calcium ions.
10. A process for the preparation of a compound of formula (I) as claimed in claim 7 , wherein the phosphorylating agent is phosphorus oxychloride.
11. A process for the preparation of a compound of formula (I) as claimed in claim 7 , wherein the phosphorylating agent is added in the presence of a base.
12. A process for the preparation of a compound of formula (I) as claimed in claim 7 , wherein the product of step i) is converted to its sodium salt prior to step ii).
13. A process for the preparation of a compound of formula (I) as claimed in claim 7 , wherein the reducing agent is hydrogen with a palladium on carbon catalyst.
14. A process for the preparation of a compound of formula (I) as claimed in claim 7 , wherein the calcium ion source is calcium acetate.
15. A process for the preparation of a compound of formula (I) as claimed in claim 7 , additionally comprising recrystallising the compound from an appropriate solvent.
16. A process for the preparation of a compound of formula (I) as claimed in claim 15 , wherein the solvent is a mixture of industrial methylated spirit and water.
17. A process for the preparation of a compound of formula (I) as claimed in claim 7 , additionally comprising heating the product in water to a temperature in the range 70 to 99° C. for 2.5 to 6 hours, then cooling to ambient temperature and harvesting to solid.
18. Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate Form (1) characterized by an X-ray powder diffraction trace substantially as shown in FIG. 1 .
19. A crystalline form of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-phosphonooxy)propylcarbamate characterised by an X-ray powder diffraction pattern expressed in terms of 2 theta angles, wherein said X-ray powder diffraction pattern has peaks that may occur at the following approximate 2 theta angles: 5.735, 9.945, 11.500, 13.780, 14.930, 15.225, 17.980, 19.745, 21.575, 22.170, 24.505 and 27.020 degrees.
20. A crystalline form of calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate characterised by an X-ray powder diffraction pattern expressed in terms of 2 theta angles and relative intensities (1),
Angle 2θ
I
5.7350
100
9.9450
38
11.1150
7
11.5000
10
13.7800
18
14.9300
10
15.2250
16
17.9800
35
19.7450
14
19.9600
5
20.8050
8
21.5750
12
22.1700
15
22.3550
7
22.9100
6
23.1350
5
24.5050
14
25.0350
2
25.2550
2
25.8600
7
26.5050
2
27.0200
10
27.7850
3
28.2150
4
28.3650
6
28.8250
2
28.9450
2
29.4150
4
30.1950
2
30.5750
3
31.1200
2
31.7950
2
32.2450
4
32.7750
3
32.8900
3
33.8150
2
34.9050
2
35.2950
3
35.8050
2
36.4600
3
36.8300
2
37.8400
2
38.6550
2
39.5350
2
39.6150
2
40.5850
3
41.3550
2
41.8100
2
42.2350
2
42.6900
3
43.2000
2
43.9200
1
44.4000
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